Clinical Research Directory

Leucine Enriched Essential Amino Acid Mixture to Reverse Muscle Loss in Cirrhosis

Loss of skeletal muscle mass or sarcopenia is the most common and potentially reversible complication in cirrhosis that increases morbidity and mortality before, during and after liver transplantation. No proven treatments exist for the prevention or reversal of sarcopenia in cirrhosis, primarily because the mechanisms responsible for this are unknown. Based on compelling preliminary studies and those of the co investigator, investigators hypothesize that the mechanism of reduced skeletal muscle mass in cirrhosis is due to a myostatin mediated impaired mTOR (mechanistic target of rapamycin) signaling resulting in reduced protein synthesis and increased autophagy. Investigators further postulate that leucine, a direct stimulant of mTOR, will reverse the impaired mTOR phosphorylation in the skeletal muscle of cirrhotics. The consequent increase in protein synthesis reduced autophagy will result in an increase in skeletal muscle mass. Investigators will test these hypotheses by quantifying the response to acute and long term (3 month) administration of leucine enriched essential amino acid (EAA/LEU) compared with an isonitrogenous isocaloric non-essential balanced amino acid mixture (does not stimulate protein synthesis) in cirrhotic patients. Fractional protein synthesis rate (FSR) in skeletal muscle, responses of the molecular regulatory pathways of skeletal muscle protein synthesis, and autophagy flux will be quantified in the acute and long term protocols. Tracer studies using L-\[D5\]-phenylalanine (Phe) as a primed constant infusion (prime 2µmol.kg-1.hr-1; constant 0.05 µmol.kg-1.hr-1) with and L \[ring-D2\] tyrosine, forearm plethysmography, and sequential skeletal muscle biopsies (total of 3 per study subject) will be used to quantify these outcomes. Anthropometric, clinical and body composition measures will be additional outcome measures for the long term intervention. Expression of regulatory signaling proteins, myostatin, IGF-1 (insulin like growth factor) , phospho-Akt, phospho-AMPK (activated protein kinase), phospho-mTOR and phospho-p70s6k will be quantified by Western immunoblots. Autophagy flux will be measured by quantifying expression of the autophagosome proteins.

RTX001 Autologous Engineered Macrophages for Liver Cirrhosis

The purpose of this study is to assess the safety and efficacy of RTX001 in patients with end-stage liver disease. This study is the first time RTX001, a macrophage cell therapy engineered to have an anti-inflammatory and anti-fibrotic effect, will be given to humans.

Liver Cancer Prevention Randomized Control Trial

To determine the effectiveness of a behaviorally-based tailored disease management intervention in patients with fibrosis or steatosis and risk factors for cirrhosis.

Testing LiverWatch, a Home-Based Remote-Monitoring Intervention for Advanced Liver Disease

Remote healthcare monitoring for cirrhosis has shown promise in overcoming barriers to accessing specialty care, improving healthcare quality, and reducing mortality. The LiverWatch study is investigating whether a remote nutrition, physical activity, and education intervention can improve health outcomes in those with cirrhosis. In this clinical trial, individuals will be randomized to either enhanced usual care or the LiverWatch intervention. Both groups are given fitbits and asked to increase their step counts. Those in the Liverwatch group will be incentivized for increase their physical activity while also undergoing a personalized nutrition intervention and weekly symptom monitoring and cirrhosis education.

Measuring Patient Reported Needs in Outpatient Liver Disease Management

This prospective study aims to assess health-related social needs (HRSNs) among patients with chronic liver disease (CLD) receiving outpatient care at Indiana University Health. Patients with CLD often face socioeconomic challenges that adversely affect health outcomes, but no validated screening tool exists for this population. The primary objective is to measure the prevalence and types of HRSNs in CLD patients. Secondary objectives are to evaluate patient preferences regarding provider involvement in addressing social needs, explore reasons for declining assistance, and assess provider perspectives on incorporating HRSN data into clinical care. A total of 200 adult patients with CLD and their visit providers will be enrolled. Participants will complete surveys on demographics, HRSNs, health literacy, quality of life, social support, and patient activation, with medical data supplemented from chart review. Providers will complete surveys about their experiences using HRSN data in routine practice. Results will describe unmet social needs in this population, patient and provider attitudes toward screening, and inform strategies for integrating HRSN assessments into liver disease management and routine healthcare delivery.

LiveSMART Trial to Prevent Falls in Patients With Cirrhosis - Supplementary Study

The LIVE-SMART supplementary study will assess social determinants of health (income, education, neighborhood deprivation), financial burden (out-of-pocket costs, productivity loss), financial distress (patient and caregiver-reported outcomes), and financial toxicity (healthcare utilization) among LIVE-SMART participants and their caregivers. Participants for this supplementary study are participants in the primary study (NCT05794555) and their caregivers.

DELIVER Study in a Population With Clinical Suspicion of Liver Cirrhosis

Owlstone Medical has demonstrated that the use of an Exogenous Volatile Organic Compound (EVOC) that targets specific metabolic processes linked to cirrhosis pathophysiology enables identification of subjects with cirrhosis with high accuracy compared to healthy controls. This approach relies on the oral administration of food additives that are metabolized in the liver resulting in volatile end-products exhaled in breath. The presence of liver cirrhosis alters the metabolism of these EVOC-probes altering the breath concentrations of the end-products. These alterations can be used to identify subjects who have a risk of having liver cirrhosis. The study is designed as a case control study comparing subjects with cirrhosis against controls originating from a group of subjects with clinical suspicion of cirrhosis. Adequate balancing of subjects across definitive, probable, possible, and absent cirrhosis groups will be assured through a recruitment enrichment strategy. The primary output of the study will be an algorithm to calculate a risk score for the presence of cirrhosis. As a secondary objective sensitivity analysis will be performed to assess the impact of subject characteristics and cirrhosis etiology on test performance to assure robustness of the test in a deployment setting. The results of this study will inform test optimization for a prospective clinical validation trial, with the goal of developing a test that is widely applicable and available in primary care centers

Development of 4D Flow MRI for Risk Stratification of Variceal Bleeding in Cirrhosis

The goal of this research is to validate novel non-invasive Magnetic resonance imaging (MRI) biomarkers to detect Gastroesophageal varices (GEV) in patients with cirrhosis, including fractional flow change in the portal vein and elevated azygos flow. End-stage liver disease (cirrhosis) is characterized by advanced fibrosis, liver failure, and portal hypertension. There are many causes of cirrhosis, including viral hepatitis, alcohol abuse, and perhaps most importantly, non-alcoholic fatty liver disease (NAFLD) and its aggressive subset, non-alcoholic steatohepatitis (NASH). 3 million new cases of end-stage liver disease (cirrhosis) are expected over the next decade. In cirrhosis, portosystemic collaterals that shunt blood away from the liver develop due to increased portal pressure. Gastroesophageal varices (GEV) are the most clinically relevant because they can cause fatal internal bleeding. GEV bleeding carries \~20% mortality at 6 weeks, and \~34% overall mortality. Identification of at-risk varices, prior to bleeding, is of paramount importance to initiate primary prophylaxis. To identify and treat at-risk patients, current guidelines recommend regular esophagogastroduodenoscopy (EGD) and variceal band ligation. Detection of high-risk GEV is key to initiating primary prophylaxis, which can reduce mortality by 50-70%. However, endoscopy is invasive and often unnecessary when no treatment is required. Therefore, the American Association for the Study of Liver Diseases has identified the development of "non-invasive markers that predict the presence of high-risk varices" as a major unmet need.

A Phase 3 Study to Evaluate the Effect of Resmetirom on Clinical Outcomes in Patients With Well-compensated NASH Cirrhosis (MAESTRO-NASH-OUTCOMES)

This study will determine the effect of oral 80 mg resmetirom administered once daily on participants with well-compensated non-alcoholic steatohepatitis (NASH) cirrhosis by measuring the time to experiencing a Composite Clinical Outcome event.

Liver Fibrosis in Zambian HIV-HBV Co-infected Patients

A cohort of adults with HIV-HBV co-infection will be created in Lusaka, Zambia, to describe the short and long-term (up to 10 years of follow-up) HBV and liver outcomes, including the effectiveness of current therapies, and to identify the risk factors for major endpoints of interest, including HCC and HBV functional cure. This cohort will also create a pool of potential participants for in-depth mechanistic studies and clinical trials of novel HBV cure drugs.

Erlotinib for Hepatocellular Carcinoma Chemoprevention

This phase II randomized placebo-controlled trial studies low-dose erlotinib treatment to assess its efficacy and safety to prevent development of hepatocellular carcinoma in patients with advanced liver fibrosis or cirrhosis.

Angiotensin 2 for AKI After OLT

Kidney injury is a common complication following liver transplantation and is associated with a higher complication rate and increased risk of death. While there are many factors that likely contribute to kidney injury in the perioperative period, a relative low serum level of angiotensin 2 (Ang 2) (a protein hormone that causes blood vessels to narrow) found in patients with liver cirrhosis (late stage of liver damage) may increase their risk of developing acute kidney injury (sudden episode of kidney failure or damage). We propose to investigate how early administration of Ang 2, a new vasopressor drug approved by the FDA in December 2017 for patients with low blood pressure, during the intra-operative period of liver transplant surgery affects the rate of kidney injury after transplantation. Patients who are deemed appropriate candidates for the study will be randomized 1:1 to the treatment and control groups. The intervention period of the study will occur in the operating room during transplant surgery and will be performed by their anesthesiologists. In the Treatment group, patients will receive Ang 2 infusions in addition to other standard vasopressors while patients in the control group will receive standard vasopressors alone. The infusion of Ang 2 in the treatment group will continue through the duration of the surgery and will be stopped prior to leaving the operating room. Both the treatment group and the control group will then be followed for 14 days to evaluate rates of kidney injury and to look for any complications. The follow up period will be extended to 28 days to look at in-hospital mortality rates in both groups. The daily follow up analysis will occur while the enrolled patients are inpatient following their transplantation surgery and will be done by looking at lab values and other data that is routinely gathered by their managing teams. This study will serve as a pilot study to evaluate feasibility of our protocol and to collect some preliminary data on the use of Ang 2 in this patient population. As such we plan to enroll approximately 30 patients who have accepted an offer to receive a donor liver. We hope to reach our goal enrollment within 5 months of starting the study.

Chronic Hepatitis B Virus Infection in Zambia

Chronic hepatitis B virus infection is a common condition in Zambia. Among Zambian blood donors, up to 8% are chronically infected with HBV. Despite the burden, awareness of HBV is low in Zambia and the Ministry of Health is in early stages of development of guidelines for HBV screening, treatment, and prevention. The purpose of this clinical cohort study is to characterize the clinical features of chronic HBV infection at UTH and describe treatment and care outcomes. The investigators will enroll 500 adults and follow the cohort for up to 5 years to assess short and long-term viral, serologic, and liver outcomes such as cirrhosis and liver cancer.

Patients With Primary Biliary Cholangitis(PBC)

Primary Biliary Cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small intrahepatic bile ducts, leading to chronic cholestasis, hepatic fibrosis, and, in advanced stages, cirrhosis. Recent advances in the understanding of PBC pathophysiology have highlighted the central role of immune, inflammatory, and metabolic alterations in disease onset and progression.

Liver Cirrhosis Network Rosuvastatin Efficacy and Safety for Cirrhosis in the United States

This is a double-blind, phase 2 study to evaluate safety and efficacy of rosuvastatin in comparison to placebo after 2 years in patients with compensated cirrhosis.

Prevalence of NAFLD and Advanced Fibrosis in Patients With Type 1 Diabetes

The aim of this study is to assess the prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 1 diabetes receiving care at Joslin clinic using noninvasive imaging and serum-based methods with the goal of identifying high-risk patients with advanced fibrosis who should be prioritized for specialty referral

Prophylactic Antibiotics in Endoscopic Secondary Prevention of Gastroesophageal Variceal Bleeding

Whether prophylactic antibiotics should be administered in the endoscopic secondary prevention of GVB or not is unclear. In this non-inferiority trial, we are aimed to evaluate whether prophylactic antibiotics are essential in the endoscopic secondary prevention of cirrhotic patients with gastroesophageal variceal bleeding.

Evidence Based Mental Wellness Programming Online for Adults Across Chronic Physical Conditions

Chronic physical conditions are defined as conditions that require ongoing management and treatment over extended periods of time. Chronic physical conditions are not only leading causes of death and disability in North America but they are commonly associated with mental distress and reduced quality of life. Online mind-body wellness programming ranging from physical activity to mindfulness interventions has been shown to be effective in improving mental wellness in a variety of chronic disease populations, but there is a need to evaluate scalable ways to deliver these programs. Building upon a previously developed online wellness program for inflammatory bowel disease (IBD) and primary biliary cholangitis (PBC), the research team has developed a mind-body wellness program for adults ≥18 years of age living with different chronic conditions (e.g., cirrhosis, PBC, heart failure). The 12-week program will be delivered online, and include follow- along mindful movement, breathwork and meditation routines, and a psychology based coping skills program. In a three-armed randomized controlled trial, the study will assess the impact on the primary outcome of anxiety and depression as measured through the hospital anxiety and depression scale (HADS). At the beginning and the end of the 12-week research study, participants will complete surveys to assess secondary/exploratory outcome measures including quality of life, fatigue, frailty, demoralization, and healthcare usage. After the program, the research team will conduct interviews with participants to allow them to share their other feedback about the program. The researchers will also send surveys to the participants eight weeks after the program ends to assess longer- term impacts on primary and secondary outcomes.

Changes in Glucose Tolerance in Patients With Cirrhosis Peri-Liver Transplant

The goal of this observational study is to establish risk factors for post-transplant in adult individuals with cirrhosis without diabetes undergoing liver transplant evaluation. The question being addressed is: can laboratory work, anthropometric tests, functional tests, imaging, and advanced measurements such as wrist actigraphy, continuous glucose monitoring, or oral glucose tolerance testing predict the development of diabetes after liver transplant? Participants will be asked to periodically participate in wearing a continuous glucose monitor and wrist actigraph and obtain an oral glucose tolerance test both before and after liver transplant.

4beta-hydroxycholesterol in Cirrhosis

The aim is to evaluate the levels of oxysterols and especially 4beta-hydroxycholesterol in patients with liver cirrhosis. Three cirrhosis cohorts are recruited: patients treated with spironolactone, patients treated with rifaximin, patients without spironolactone or rifaximin. Also three other control cohorts are recruited: patients with pneumonia, patients with Crohn's disease, patients with ulcerative colitis. The effect of the cirrhosis and its medications spironolactone and rifaximin are compared to control groups.

SGLT-2 Inhibitors in the Treatment of Ascites

The goal of this observational study is to test the efficacy of glyphozines (SGLT-2 inhibitors) in the control of ascites in patients with liver cirrhosis in class A6-B9, according to the Child-Pugh classification, and type 2 diabetes mellitus. The investigators will compare patients belonging to the intervention group (A), who will be given SGLT-2 inhibitors according to diabetology indications in addition to standard medical therapy for 6, with patients of the control group (B), who will, instead, continue with the standard medical therapy for 6 months. Standard medical therapy will include dietary sodium restriction, treatment with diuretics (furosemide and spironolactone), hypoglycemic therapy (metformin, insulin, or both) and other supportive care. The main questions aims of this study are: 1. Compare the efficacy and safety of a therapeutic approach based on the administration of SGLT-2 inhibitors in addition to optimal medical therapy (MRA and loop diuretic) compared to traditional diuretic therapy only, in cirrhotic patients with saline retention and diabetes. 2. Demonstrate better control of the glycemic profile in cirrhotic diabetic patients using SGLT-2 inhibitors.

Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of Oesophageal Varices Trial.

Research has proven that large varices can be treated with beta-blockers (a type of anti-hypertensive medication) to reduce the pressure in the veins. The management of small varices is still uncertain. This study aims to discover if beta blockers can be used in this setting. We hypothesize that beta blockers will reduce the risk of bleeding from small varices from 20% to 10% over a period of 3 years, resulting in significant cost savings to the NHS from better patient outcomes.

Safety and Efficacy of Ketogenic Diet for Promoting Weight Loss in Obese Individuals With Compensated NASH Cirrhosis

This is an open-label, randomized study comparing a monitored ketogenic diet intervention using standard ketogenic diet (SKD) and standard of care (SOC) dietary recommendations for 16 weeks. Subjects enrolled in the standard of care group will receive a voucher to Weight Watchers after study completion.

Prehabilitation for Patients Awaiting Liver Transplantation

This study will assess the feasibility, safety and effectiveness of a structured prehabilitation program combining exercise training, nutritional optimization and psychological support for patients with cirrhosis awaiting liver transplantation.